Abstract
Each year over 90 million units of blood are transfused worldwide. Our dependence on this blood supply mandates optimized blood management and storage. During storage, red blood cells undergo degenerative processes resulting in altered metabolic characteristics which may make blood less viable for transfusion. However, not all stored blood spoils at the same rate, a difference that has been attributed to variable rates of energy usage and metabolism in red blood cells. Specific metabolite abundances are heritable traits; however, the link between heritability of energy metabolism and red blood cell storage profiles is unclear. Herein we performed a comprehensive metabolomics and proteomics study of red blood cells from 18 mono- and di-zygotic twin pairs to measure heritability and identify correlations with ATP and other molecular indices of energy metabolism. Without using affinity-based hemoglobin depletion, our work afforded the deepest multi-omic characterization of red blood cell membranes to date (1280 membrane proteins and 330 metabolites), with 119 membrane protein and 148 metabolite concentrations found to be over 30% heritable. We demonstrate a high degree of heritability in the concentration of energy metabolism metabolites, especially glycolytic metabolites. In addition to being heritable, proteins and metabolites involved in glycolysis and redox metabolism are highly correlated, suggesting that crucial energy metabolism pathways are inherited en bloc at distinct levels. We conclude that individuals can inherit a phenotype composed of higher or lower concentrations of these proteins together. This can result in vastly different red blood cells storage profiles which may need to be considered to develop precise and individualized storage options. Beyond guiding proper blood storage, this intimate link in heritability between energy and redox metabolism pathways may someday prove useful in determining the predisposition of an individual toward metabolic diseases.
Highlights
From the ‡Integrated Program in Biochemistry, §Biomolecular Chemistry, ¶Departments of Chemistry, ʈPathology and Laboratory Medicine, and **Genome Center, University of Wisconsin, Madison, Wisconsin, 53706; ‡‡Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, Iowa 52242; §§Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195
We show that in red blood cells (RBCs) the concentrations of components in crucial energy metabolism pathways are inherited en bloc at distinct levels
The first step to calculating heritability is using the one-way model of intraclass correlation coefficient (ICC) to determine the similarity of a measure in a twin pair: ICC ϭ (MSbetween - MSwithin)/(MSbetween ϩ MSwithin), where MSbetween is the estimate of the mean-square variance between all twin-pairs and MSwithin is the estimate of the mean-square variance within the sets of pairs in that group [13]
Summary
Twin Subject Enrollment and Sample Collection—This report is a continuation of twin studies reported previously and utilized the same study subjects [14, 16, 31, 32]. Each subject donated one unit of whole blood which were processed according to standard operating procedures into a leukocyte-reduced RBC unit in CP2D/AS-3 extended storage media (Hemonetics Corp, Braintree, MA). The AS-3 preserved RBCs were sampled by sterile docking of tubing to the RBC unit, back-filling the tubing with RBCs and sectioning into segments This procedure was performed on the first day after donation. Sample Preparation for Proteomic Analysis— Proteolytic Digestion—A 50 l aliquot of red blood cells lysed in 500 l DI water was centrifuged at 4 °C for 30 min at 5 G. The first step to calculating heritability is using the one-way model of intraclass correlation coefficient (ICC) to determine the similarity of a measure in a twin pair: ICC ϭ (MSbetween - MSwithin)/(MSbetween ϩ MSwithin), where MSbetween is the estimate of the mean-square variance between all twin-pairs and MSwithin is the estimate of the mean-square variance within the sets of pairs in that group [13]. Once ICC values were calculated, heritability was estimated using the method derived by Newman et al, h2 ϭ (ICCMZ - ICCDZ)/(1 - ICCDZ) [39]
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